STKE Cells monitor how well the synthesis of proteins in the endoplasmic reticulum (ER) is going, and when stressful conditions cause the accumulation of unfolded proteins, the unfolded protein response (UPR) is initiated. Ito et al. used a microarray screen to detect genes whose products were expressed specifically in response to an agent causing ER stress. They identified stanniocalcin 2 ( STC2 ), which is related to a hormone originally described in fish that functions to prevent hypercalcemia. Expression of STC2 was increased in cultured cells undergoing the UPR after exposure to thapsigargin, an inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase. Like other UPR genes, STC2 was also expressed in rat brain tissue after transient cerebral ischemia. Expression of STC2 appears to require signaling from the PERK serine-threonine kinase, a known mediator of the UPR, to the transcription factor ATF4, because mouse embryo fibroblasts lacking PERK or ATF4 failed to increase expression of STC2. Increased synthesis of STC2, which was secreted from cells undergoing ER stress, appears to contribute to signaling mechanisms that help protect cells under stressful conditions. — LBR Mol. Cell. Biol. 24 , 9456 (2004).